The Emory Alcohol and Lung Biology Center formally began on January 1, 2003, and has since continued to expand its dynamic research and training environment to study the mechanisms by which alcohol abuse impacts lung health. Center investigators began with the novel observation that alcohol abuse increases the risk of developing acute lung injury and respiratory failure following sepsis, trauma, and other severe inflammatory illnesses. In fact, based on two large epidemiologic studies published by Center investigators, one can estimate that alcohol abuse is a causative factor in as many as 50-75,000 cases of acute lung injury in the U.S. each year. Further, with a mortality of -50% even with state-of-the-art care, alcohol-mediated susceptibility to acute lung injury claims tens of thousands of lives annually. Center investigators were the first to identify in both experimental models and in human subjects that chronic alcohol ingestion, even in the absence of any clinically detectable pulmonary impairment, causes severe oxidant stress in the airway that renders the lung susceptible to injury. In this competitive renewal the Center investigators hypothesize that alcohol-induced oxidant stress promotes a shift in the signaling balance between granulocyte//macrophage colony-stimulating factor (GM-CSF) and transforming growth factor p-, (TGFp-,) to one that favors the proinjurious influences of TGFfa over the normal priming stimulation by GM-CSF. The investigators further hypothesize that this imbalance, in parallel with the chronic oxidant stress, changes the phenotype of the lung such that it is more susceptible to acute lung injury as well as to other lung diseases including asthma, pneumonia, and airway fibrosis. In addition, alcohol-induced oxidant stress during gestation may render neonates vulnerable to critical illnesses, particularly in the setting of premature delivery when the lungs are not fully developed. In this competitive renewal, the Center will extend its previous findings and examine the discrete molecular mechanisms by which alcohol abuse disrupts normal cellular function in the adult and neonatal lung, and identify novel therapeutic interventions that can decrease the morbidity and mortality associated with the alcoholic lung. The Center has more than doubled in size since it began four years ago, and through its collaborative interactions can advance the study of alcohol-related lung diseases and continue to train the next generation of alcohol researchers dedicated to improving lung health.